Implantable neurostimulator-implemented method for managing hypertension through renal denervation and vagus nerve stimulation

ABSTRACT

A method for managing hypertension through renal nerve denervation and vagus nerve stimulation is provided. Renal nerves are disrupted to inhibit a sympathetic nervous system. Thereafter, an implantable neurostimulator, including a pulse generator, is configured to deliver electrical therapeutic stimulation in a manner that results in creation and propagation (in both afferent and efferent directions) of action potentials within neuronal fibers of a patient&#39;s cervical vagus nerve. A maintenance dose of the electrical therapeutic stimulation is delivered to the vagus nerve via the pulse generator to restore cardiac autonomic balance through continuously-cycling, intermittent and periodic electrical pulses.

FIELD

This application relates in general to chronic cardiac dysfunctiontherapy.

BACKGROUND

Hypertension is a condition in which blood pressure in the blood vesselsis persistently elevated. Blood pressure is the force of blood pushingagainst blood vessel walls. The higher the blood pressure, the harderthe heart must work to circulate blood through the blood vessels.Chronic high blood pressure can lead to kidney failure, heart failure,blood vessel damage, stroke, and eye damage, among other illnesses thatmay cause shortened life expectancy. Accordingly, it is beneficial tokeep blood pressure under control.

Congestive heart failure (CHF) and other forms of chronic cardiacdysfunction (CCD) may be related to an autonomic imbalance of thesympathetic and parasympathetic nervous systems that, if left untreated,can lead to cardiac arrhythmogenesis, progressively worsening cardiacfunction and eventual patient death. CHF is pathologically characterizedby an elevated neuroexitatory state and is accompanied by physiologicalindications of impaired arterial and cardiopulmonary baroreflex functionwith reduced vagal activity.

CHF triggers compensatory activations of the sympathoadrenal(sympathetic) nervous system and the renin-angiotensin-aldosteronehormonal system, which initially help to compensate for deterioratingheart-pumping function, yet, over time, can promote progressive leftventricular dysfunction and deleterious cardiac remodeling. Patientssuffering from CHF are at increased risk of tachyarrhythmias, such asatrial fibrillation (AF), ventricular tachyarrhythmias (ventriculartachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter,particularly when the underlying morbidity is a form of coronary arterydisease, cardiomyopathy, mitral valve prolapse, or other valvular heartdisease. Sympathoadrenal activation also significantly increases therisk and severity of tachyarrhythmias due to neuronal action of thesympathetic nerve fibers in, on, or around the heart and through therelease of epinephrine (adrenaline), which can exacerbate analready-elevated heart rate.

The standard of care for managing CCD in general continues to evolve.For instance, new therapeutic approaches that employ electricalstimulation of neural structures that directly address the underlyingcardiac autonomic nervous system imbalance and dysregulation have beenproposed. In one form, controlled stimulation of the cervical vagusnerve beneficially modulates cardiovascular regulatory function.Currently, vagus nerve stimulation (VNS) is only approved for theclinical treatment of drug-refractory epilepsy and depression, althoughVNS has been proposed as a therapeutic treatment of heart conditionssuch as CHF. For instance, VNS has been demonstrated in canine studiesas efficacious in simulated treatment of AF and heart failure, such asdescribed in Zhang et al., “Therapeutic Effects of SelectiveAtrioventricular Node Vagal Stimulation in Atrial Fibrillation and HeartFailure,” J. Cardiovasc. Electrophysiol., Vol. pp. 1-6 (Jul. 9, 2012),the disclosure of which is incorporated by reference.

Conventional general therapeutic alteration of cardiac vagal efferentactivation through electrical stimulation targets only the efferentnerves of the parasympathetic nervous system, such as described inSabbah et al., “Vagus Nerve Stimulation in Experimental Heart Failure,”Heart Fail. Rev., 16:171-178 (2011), the disclosure of which isincorporated by reference. The Sabbah paper discusses canine studiesusing a vagus nerve stimulation system, manufactured by BioControlMedical Ltd., Yehud, Israel, which includes an electrical pulsegenerator, right ventricular endocardial sensing lead, and right vagusnerve cuff stimulation lead. The sensing lead enables stimulation of theright vagus nerve in a highly specific manner, which involvesclosed-loop synchronization of the vagus nerve stimulation pulse to thecardiac cycle. An asymmetric tri-polar nerve cuff electrode is implantedon the right vagus nerve at the mid-cervical position. The electrodeprovides cathodic induction of action potentials while simultaneouslyapplying asymmetric anodal blocks that lead to preferential activationof vagal efferent fibers. Electrical stimulation of the right cervicalvagus nerve is delivered only when heart rate increases beyond a presetthreshold. Stimulation is provided at an impulse rate and intensityintended to reduce basal heart rate by ten percent by preferentialstimulation of efferent vagus nerve fibers leading to the heart whileblocking afferent neural impulses to the brain. Although effective inpartially restoring baroreflex sensitivity and, in the canine model,increasing left ventricular ejection fraction and decreasing leftventricular end diastolic and end systolic volumes, the degree oftherapeutic effect on parasympathetic activation occurs throughincidental recruitment of afferent parasympathetic nerve fibers in thevagus, as well as through recruitment of efferent fibers. Efferentstimulation alone is less effective at restoring autonomic balance thanbi-directional stimulation.

Other uses of electrical nerve stimulation for therapeutic treatment ofvarious cardiac and physiological conditions are described. Forinstance, U.S. Pat. No. 6,600,954, issued Jul. 29, 2003 to Cohen et al.discloses a method and apparatus for selective control of nerve fiberactivations. An electrode device is applied to a nerve bundle capable ofgenerating, upon activation, unidirectional action potentials thatpropagate through both small diameter and large diameter sensory fibersin the nerve bundle, and away from the central nervous system. Thedevice is particularly useful for reducing pain sensations in the legsand arms.

U.S. Pat. No. 6,684,105, issued Jan. 27, 2004 to Cohen et al. disclosesan apparatus for treatment of disorders by unidirectional nervestimulation. An apparatus for treating a specific condition includes aset of one or more electrode devices that are applied to selected sitesof the central or peripheral nervous system of the patient. For someapplications, a signal is applied to a nerve, such as the vagus nerve,to stimulate efferent fibers and treat motility disorders, or to aportion of the vagus nerve innervating the stomach to produce asensation of satiety or hunger. For other applications, a signal isapplied to the vagus nerve to modulate electrical activity in the brainand rouse a comatose patient, or to treat epilepsy and involuntarymovement disorders.

U.S. Pat. No. 7,123,961, issued Oct. 17, 2006 to Kroll et al. disclosesstimulation of autonomic nerves. An autonomic nerve is stimulated toaffect cardiac function using a stimulation device in electricalcommunication with the heart by way of three leads suitable fordelivering multi-chamber stimulation and shock therapy. For arrhythmiadetection, the device utilizes atrial and ventricular sensing circuitsto sense cardiac signals to determine whether a rhythm is physiologic orpathologic. The timing intervals between sensed events are classified bycomparing them to a predefined rate zone limit and other characteristicsto determine the type of remedial therapy needed, which includesbradycardia pacing, anti-tachycardia pacing, cardioversion shocks(synchronized with an R-wave), or defibrillation shocks (deliveredasynchronously).

U.S. Pat. No. 7,225,017, issued May 29, 2007 to Shelchuk disclosesterminating VT in connection with any stimulation device that isconfigured or configurable to stimulate nerves, or stimulate and shock apatient's heart. Parasympathetic stimulation is used to augmentanti-tachycardia pacing, cardioversion, or defibrillation therapy. Tosense atrial or ventricular cardiac signals and provide chamber pacingtherapy, particularly on the left side of the patient's heart, thestimulation device is coupled to a lead designed for placement in thecoronary sinus or its tributary veins. Cardioversion stimulation isdelivered to a parasympathetic pathway upon detecting a ventriculartachycardia. A stimulation pulse is delivered via the lead to one ormore electrodes positioned proximate to the parasympathetic pathwayaccording to stimulation pulse parameters based on the probability ofreinitiation of an arrhythmia.

U.S. Pat. No. 7,277,761, issued Oct. 2, 2007 to Shelchuk discloses vagalstimulation for improving cardiac function in heart failure patients. Anautonomic nerve is stimulated to affect cardiac function using astimulation device in electrical communication with the heart by way ofthree leads suitable for delivering multi-chamber endocardialstimulation and shock therapy. Where the stimulation device is intendedto operate as an implantable cardioverter-defibrillator (ICD), thedevice detects the occurrence of an arrhythmia, and applies a therapy tothe heart aimed at terminating the detected arrhythmia. Defibrillationshocks are generally of moderate to high energy level, deliveredasynchronously, and pertaining exclusively to the treatment offibrillation.

U.S. Pat. No. 7,295,881, issued Nov. 13, 2007 to Cohen et al. disclosesnerve branch-specific action potential activation, inhibition andmonitoring. Two preferably unidirectional electrode configurations flanka nerve junction from which a preselected nerve branch issues,proximally and distally to the junction, with respect to the brain.Selective nerve branch stimulation can be used with nerve-branchspecific stimulation to achieve selective stimulation of a specificrange of fiber diameters, restricted to a preselected nerve branch,including heart rate control, where activating only the vagal B nervefibers in the heart, and not vagal A nerve fibers that innervate othermuscles, can be desirous.

U.S. Pat. No. 7,778,703, issued Aug. 17, 2010 to Gross et al. disclosesselective nerve fiber stimulation for treating heart conditions. Anelectrode device is adapted to be coupled to a vagus nerve of a subjectand a control unit drives the electrode device by applying stimulatingand inhibiting currents to the vagus nerve, which are capable ofrespectively inducing action potentials in a therapeutic direction in afirst set and a second set of nerve fibers in the vagus nerve andinhibiting action potentials in the therapeutic direction in the secondset of nerve fibers only. The nerve fibers in the second set have largerdiameters than the nerve fibers in the first set. Typically, the systemis configured to treat heart failure or heart arrhythmia, such as atrialfibrillation or tachycardia by slowing or stabilizing the heart rate, orreducing cardiac contractility.

U.S. Pat. No. 7,813,805, issued Oct. 12, 2010 to Farazi and U.S. Pat.No. 7,869,869, issued Jan. 11, 2011 to Farazi both disclose subcardiacthreshold vagus nerve stimulation. A vagus nerve stimulator isconfigured to generate electrical pulses below a cardiac threshold,which are transmitted to a vagus nerve, so as to inhibit or reduceinjury resulting from ischemia. For arrhythmia detection, a heartstimulator utilizes atrial and ventricular sensing circuits to sensecardiac signals to determine whether a rhythm is physiologic orpathologic. In low-energy cardioversion, an ICD device typicallydelivers a cardioversion stimulus synchronously with a QRS complex;thus, avoiding the vulnerable period of the T-wave and avoiding anincreased risk of initiation of VF. In general, if anti-tachycardiapacing or cardioversion fails to terminate a tachycardia, then, forexample, after a programmed time interval or if the tachycardiaaccelerates, the ICD device initiates defibrillation therapy.

Finally, U.S. Pat. No. 7,885,709, issued Feb. 8, 2011 to Ben-Daviddiscloses nerve stimulation for treating disorders. A control unitdrives an electrode device to stimulate the vagus nerve, so as to modifyheart rate variability, or to reduce heart rate, by suppressing theadrenergic (sympathetic) system. Typically, the system is configured totreat heart failure or heart arrhythmia, such as atrial fibrillation ortachycardia. In one embodiment, a control unit is configured to drive anelectrode device to stimulate the vagus nerve, so as to modify heartrate variability to treat a condition of the subject. Therapeuticeffects of reduction in heart rate variability include the narrowing ofthe heart rate range, thereby eliminating very slow heart rates and veryfast heart rates. For this therapeutic application, the control unit istypically configured to reduce low-frequency heart rate variability, andto adjust the level of stimulation applied based on the circadian andactivity cycles of the subject. Therapeutic effects also includemaximizing the mechanical efficiency of the heart by maintainingrelatively constant ventricular filling times and pressures. Forexample, this therapeutic effect may be beneficial for subjectssuffering from atrial fibrillation, in which fluctuations in heartfilling times and pressure reduce cardiac efficiency.

Accordingly, a need remains for an approach to therapeutically treatinghypertension to improve autonomic balance and cardiovascular regulatoryfunction.

SUMMARY

Hypertension is a significant risk factor for coronary artery disease,myocardial infarction, and stroke. Hypertension has been linked tocardiovascular mortality and morbidity. Hypertension induces leftventricular hypertrophy and cardiac fibrosis and is associated withchronic kidney disease. Excessive sustained activation of thesympathetic nervous system is believed to have a deleterious effect onlong term cardiac performance and increases the risk of hypertension.Bi-directional afferent and efferent neural stimulation through thevagus nerve can beneficially restore autonomic balance and improve longterm clinical outcome. The neural stimulation is provided in a low levelmaintenance dose independent of cardiac cycle.

Renal denervation is a procedure for ablating renal nerves or otherneural fibers that contribute to renal neural function. Such procedurehas been shown to assist in the regulation of hypertension. A renaldenervation procedure may, for example, be accomplished in less than anhour, and may comprise positioning a steerable catheter in the renalartery. A pulse generator is used to deliver radio frequency (RF) energyto the renal artery via an RF electrode on the catheter. The RF energyis delivered along each renal artery to achieve denervation anddisruption to the sympathetic and parasympathetic nervous systems. Suchrenal denervation can be performed using a minimally invasive procedurethat does not require a permanent implant.

In accordance with embodiments of the present invention, a combinationtherapy of therapeutic VNS delivered prior to or following renaldenervation provides systemic chronic management of hypertension.Therapeutic VNS directly improves left ventricular function bystimulation of the vagal afferent and efferent fibers thereby restoringautonomic balance and improving central blood pressure. Renaldenervation further modulates the elevated sympathetic activity both byreducing efferent renal sympathetic control of kidney function and byremoving the renal afferent sympathetic contribution to central bloodpressure control.

One embodiment includes disrupting renal nerves to inhibit a sympatheticnervous system and further includes an implantableneurostimulator-implemented method for managing hypertension throughvagus nerve stimulation. The renal nerves may be disrupted bypositioning a catheter within a renal artery; positioning at least oneelectrode of the catheter proximate to at least one of the renal nerves;energizing the at least one electrode; and removing the catheter fromwithin the renal artery. An implantable neurostimulator, including apulse generator, is configured to deliver electrical therapeuticstimulation in a manner that results in creation and propagation (inboth afferent and efferent directions) of action potentials withinneuronal fibers comprising the cervical vagus nerve of a patient.Operating modes are stored in the pulse generator. A maintenance dose ofthe electrical therapeutic stimulation is parametrically defined andtuned to restore cardiac autonomic balance through continuously-cycling,intermittent and periodic electrical pulses. The maintenance dose istherapeutically delivered to the vagus nerve independent of cardiaccycle via a pulse generator included in the implantable neurostimulatorthrough, for example, a pair of helical electrodes electrically coupledto the pulse generator via a nerve stimulation therapy lead.

By improving autonomic balance and cardiovascular regulatory function,therapeutic VNS and renal denervation operate acutely to decrease heartrate, reflexively increase heart rate variability and coronary flow,reduce cardiac workload through vasodilation, and improve leftventricular relaxation without aggravating comorbid tachyarrhythmia orother cardiac arrhythmic conditions. Over the long term, low dosage VNSprovides the chronic benefits of decreased negative cytokine production,increased baroreflex sensitivity, increased respiratory gas exchangeefficiency, favorable gene expression, renin-angiotensin-aldosteronesystem down-regulation, and anti-arrhythmic, anti-apoptotic, andectopy-reducing anti-inflammatory effects.

Still other embodiments of the present invention will become readilyapparent to those skilled in the art from the following detaileddescription, wherein are described embodiments by way of illustratingthe best mode contemplated for carrying out the invention. As will berealized, the invention is capable of other and different embodimentsand its several details are capable of modifications in various obviousrespects, all without departing from the spirit and the scope of thepresent invention. Accordingly, the drawings and detailed descriptionare to be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patientin conjunction with an operation of a renal denervation device, inaccordance with one embodiment.

FIGS. 2A and 2B are diagrams respectively showing the implantableneurostimulator and the simulation therapy lead of FIG. 1.

FIG. 3 is a diagram showing an external programmer for use with theimplantable neurostimulator of FIG. 1.

FIG. 4 is a diagram showing electrodes provided as on the stimulationtherapy lead of FIG. 2 in place on a vagus nerve in situ.

FIG. 5 is a graph showing, by way of example, the relationship betweenthe targeted therapeutic efficacy and the extent of potential sideeffects resulting from use of the implantable neurostimulator of FIG. 1.

FIG. 6 is a graph showing, by way of example, the optimal duty cyclerange based on the intersection depicted in FIG. 3.

FIG. 7 is a timing diagram showing, by way of example, a stimulationcycle and an inhibition cycle of VNS as provided by implantableneurostimulator of FIG. 1.

FIG. 8 is a flow diagram showing an implantable neurostimulatorimplementation and renal denervation method for managing hypertensionthrough vagus nerve stimulation and renal nerve ablation, in accordancewith one embodiment.

DETAILED DESCRIPTION

Changes in autonomic control of the cardiovascular systems of patientssuffering from CHF and other cardiovascular diseases cause fluctuationsin the autonomic nervous system, favoring increased sympathetic anddecreased parasympathetic central outflow. These fluctuations areaccompanied by pronounced elevation of basal heart rate arising fromchronic sympathetic hyperactivation along the neurocardiac axis.

Peripheral neurostimulation therapies that target the fluctuations ofthe autonomic nervous system have been shown to improve clinicaloutcomes in some patients. Specifically, autonomic regulation therapyresults in simultaneous creation and propagation of efferent andafferent action potentials within nerve fibers comprising the cervicalvagus nerve. The therapy directly restores autonomic balance by engagingboth medullary and cardiovascular reflex control components of theautonomic nervous system. Upon stimulation of the cervical vagus nerve,action potentials propagate away from the stimulation site in twodirections, efferently toward the heart and efferently toward the brain.Efferent action potentials influence the intrinsic cardiac nervoussystem and the heart and other organ systems, while afferent actionpotentials influence central elements of the nervous system.

An implantable vagus nerve stimulator with integrated heart rate sensor,such as used to treat drug-refractory epilepsy and depression, can beadapted for use in managing hypertension through therapeuticbi-directional vagal stimulation. FIG. 1 is a front anatomical diagramshowing, by way of example, placement of an implantable medical device(e.g., vagus nerve stimulation (VNS) system 11) in a male patient 10, inaccordance with embodiments of the present invention. The VNS providedthrough the stimulation system 11 operates under several mechanisms ofaction. These mechanisms include increasing parasympathetic outflow andinhibiting sympathetic effects by inhibiting norepinephrine release andadrenergic receptor activation. More importantly, VNS triggers therelease of the endogenous neurotransmitter, acetylcholine (ACh), intothe synaptic cleft, which has several beneficial anti-arrhythmic,anti-apoptotic, and ectopy-reducing anti-inflammatory effects.

The implantable vagus stimulation system 11 includes at least threeimplanted components, an implantable neurostimulator or generator 12comprising a pulse generator, a therapy lead assembly 13, and electrodes14. The electrodes 14 may be provided in a variety of forms, such as,e.g., helical electrodes, probe electrodes, cuff electrodes, as well asother types of electrodes. The implantable vagus stimulation system 11can be remotely accessed following implant through an externalprogrammer, as seen in FIG. 3, by which the neurostimulator 12 can beremotely checked and programmed by healthcare professionals. Forexample, an external magnet may provide basic controls, such asdescribed in commonly assigned U.S. Pat. No. 8,600,505, entitled“Implantable Device For Facilitating Control Of Electrical StimulationOf Cervical Vagus Nerves For Treatment Of Chronic Cardiac Dysfunction,”the disclosure of which is incorporated by reference. For furtherexample, an electromagnetic controller may enable the patient 10 orhealthcare professional to exercise increased control over therapydelivery and suspension, such as described in commonly-assigned U.S.Pat. No. 8,571,654, entitled “Vagus Nerve Neurostimulator With MultiplePatient-Selectable Modes For Treating Chronic Cardiac Dysfunction,” thedisclosure of which is incorporated by reference. For further example,the external programmer may communicate with the neurostimulation system11 via other wired or wireless communication methods, such as, e.g.,wireless RF transmission. Together, the implantable vagus stimulationsystem 11 and one or more of the external components form a VNStherapeutic delivery system.

The neurostimulator 12 is typically implanted in the patient's right orleft pectoral region generally on the same side (ipsilateral) as thevagus nerve 15, 16 to be stimulated, although otherneurostimulator-vagus nerve configurations, including contra-lateral andbi-lateral are possible. A vagus nerve typically comprises two branchesthat extend from the brain stem respectively down the left side andright side of the patient, as seen in FIG. 1. The electrodes 14 aregenerally implanted on the vagus nerve 15, 16 about halfway between theclavicle 19 a-b and the mastoid process. The therapy lead assembly 13and electrodes 14 are implanted by first exposing the carotid sheath andchosen branch of the vagus nerve 15, 16 through a latero-cervicalincision (perpendicular to the long axis of the spine) on theipsilateral side of the patient's neck 18. The helical electrodes 14 arethen placed onto the exposed nerve sheath and tethered. A subcutaneoustunnel is formed between the respective implantation sites of theneurostimulator 12 and helical electrodes 14, through which the therapylead assembly 13 is guided to the neurostimulator 12 and securelyconnected.

In one embodiment, the neural stimulation is provided as a low levelmaintenance dose independent of cardiac cycle. The stimulation system 11bi-directionally stimulates either the left vagus nerve 15 or the rightvagus nerve 16, dependent upon which side of the patient's body anelectrode was implanted. However, it is contemplated that multipleelectrodes 14 and multiple leads 13 could be utilized to stimulatesimultaneously, alternatively or in other various combinations.Stimulation may be through multimodal application ofcontinuously-cycling, intermittent and periodic electrical stimuli,which are parametrically defined through stored stimulation parametersand timing cycles. Both sympathetic and parasympathetic nerve fibers arestimulated. Generally, cervical vagus nerve stimulation results inpropagation of action potentials from the site of stimulation in abi-directional manner. The application of bi-directional propagation inboth afferent and efferent directions of action potentials withinneuronal fibers comprising the cervical vagus nerve restores cardiacautonomic balance. Afferent action potentials propagate toward theparasympathetic nervous system's origin in the medulla in the nucleusambiguus, nucleus tractus solitarius, and the dorsal motor nucleus, aswell as towards the sympathetic nervous system's origin in theintermediolateral cell column of the spinal cord. Efferent actionpotentials propagate toward the heart 17 to activate the components ofthe heart's intrinsic nervous system. Either the left or right vagusnerve 15, 16 can be stimulated by the stimulation system 11. The rightvagus nerve 16 has a moderately lower (approximately 30%) stimulationthreshold than the left vagus nerve 15 for heart rate affects at thesame stimulation frequency and pulse width.

The VNS therapy is delivered autonomously to the patient's vagus nerve15, 16 through three implanted components that include a neurostimulator12, therapy lead assembly 13, and electrodes 14. FIGS. 2A and 2B arediagrams respectively showing the implantable neurostimulator 12 and thetherapy lead assembly 13 of FIG. 1. In one embodiment, theneurostimulator 12 can be adapted from a VNS Therapy AspireSR Model 106pulse generator, manufactured and sold by Cyberonics, Inc., Houston,Tex., although other manufactures and types of implantable VNSneurostimulators could also be used. The therapy lead assembly 13 andelectrodes 14 are generally fabricated as a combined assembly and can beadapted from a Model 302 lead, PerenniaDURA Model 303 lead, orPerenniaFLEX Model 304 lead, also manufactured and sold by Cyberonics,Inc., in two sizes based, for example, on a helical electrode innerdiameter, although other manufactures and types of single-pinreceptacle-compatible therapy leads and electrodes could also be used.

Referring first to FIG. 2A, the system 20 may be configured to providemultimodal vagal stimulation. In a maintenance mode, the neurostimulator12 is parametrically programmed to deliver continuously-cycling,intermittent and periodic ON-OFF cycles of VNS. Such delivery producesaction potentials in the underlying nerves that propagatebi-directionally.

The neurostimulator 12 includes an electrical pulse generator that istuned to restore autonomic balance by triggering action potentials thatpropagate both efferently and efferently within the vagus nerve 15, 16.The neurostimulator 12 is enclosed in a hermetically sealed housing 21constructed of a biocompatible, implantation-safe material, such astitanium. The housing 21 contains electronic circuitry 22 powered by abattery 23, such as a lithium carbon monoflouride battery primarybattery or a rechargeable secondary cell battery. The electroniccircuitry 22 may be implemented using complementary metal oxidesemiconductor integrated circuits that include a microprocessorcontroller that executes a control program according to storedstimulation parameters and timing cycles; a voltage regulator thatregulates system power; logic and control circuitry, including arecordable memory 29 within which the stimulation parameters are stored,that controls overall pulse generator function, receives and implementsprogramming commands from the external programmer, or other externalsource, collects and stores telemetry information, processes sensoryinput, and controls scheduled and sensory-based therapy outputs; atransceiver that remotely communicates with the external programmerusing radio frequency signals; an antenna, which receives programminginstructions and transmits the telemetry information to the externalprogrammer; and a reed switch 30 that provides remote access to theoperation of the neurostimulator 12 using an external programmer, asimple patient magnet, or an electromagnetic controller. The recordablememory 29 can include both volatile (dynamic) and persistent (static)forms of memory, such as firmware within which the stimulationparameters and timing cycles can be stored. Other electronic circuitryand components are possible.

The neurostimulator 12 includes a header 24 to securely receive andconnect to the therapy lead assembly 13. In one embodiment, the header24 encloses a receptacle 25 into which a single pin for the therapy leadassembly 13 can be received, although two or more receptacles could alsobe provided, along with the corresponding electronic circuitry 22. Theheader 24 internally includes a lead connector block (not shown) and aset of screws 26.

The housing 21 may also contain a heart rate sensor 31 that iselectrically interfaced with the logic and control circuitry, whichreceives the patient's sensed heart rate as sensory inputs. The heartrate sensor 31 monitors heart rate using an ECG-type electrode. Throughthe electrode, the patient's heart beat can be sensed by detectingventricular depolarization. In a further embodiment, a plurality ofelectrodes can be used to sense voltage differentials between electrodepairs, which can undergo signal processing for cardiac physiologicalmeasures, for instance, detection of the P-wave, QRS complex, andT-wave. The heart rate sensor 31 provides the sensed heart rate to thecontrol and logic circuitry as sensory inputs that can be used todetermine the onset or presence of arrhythmias, particularly VT.

Referring next to FIG. 2B, the therapy lead assembly 13 delivers anelectrical signal from the neurostimulator 12 to the vagus nerve 15, 16via the electrodes 14. On a proximal end, the therapy lead assembly 13has a lead connector 27 that transitions an insulated electrical leadbody to a metal connector pin 28. During implantation, the connector pin28 is guided through the receptacle 25 into the header 24 and securelyfastened in place using the set screws 26 to electrically couple thetherapy lead assembly 13 to the neurostimulator 12. On a distal end, thetherapy lead assembly 13 terminates with the electrode 14, whichbifurcates into a pair of anodic and cathodic electrodes 62 (as furtherdescribed infra with reference to FIG. 4). In one embodiment, the leadconnector 27 is manufactured using silicone and the connector pin 28 ismade of stainless steel, although other suitable materials could beused, as well. The insulated lead body 13 utilizes a silicone-insulatedalloy conductor material.

In some embodiments, the electrodes 14 are helical and placed around thecervical vagus nerve 15, 16 at the location below where the superior andinferior cardiac branches separate from the cervical vagus nerve. Inalternative embodiments, the helical electrodes may be placed at alocation above where one or both of the superior and inferior cardiacbranches separate from the cervical vagus nerve. In one embodiment, thehelical electrodes 14 are positioned around the patient's vagus nerveoriented with the end of the helical electrodes 14 facing the patient'shead. In an alternate embodiment, the helical electrodes 14 arepositioned around the patient's vagus nerve 15, 16 oriented with the endof the helical electrodes 14 facing the patient's heart 17. At thedistal end, the insulated electrical lead body 13 is bifurcated into apair of lead bodies that are connected to a pair of electrodes proper.The polarity of the electrodes could be configured into a monopolarcathode, a proximal anode and a distal cathode, or a proximal cathodeand a distal anode.

The neurostimulator 12 may be interrogated prior to implantation andthroughout the therapeutic period with a healthcare provider-operableexternal programmer and programming wand (not shown) for checking properoperation, downloading recorded data, diagnosing problems, andprogramming operational parameters, such as described incommonly-assigned U.S. Pat. Nos. 8,600,505 and 8,571,654, cited supra.FIG. 3 is a diagram showing an external programmer 40 for use with theimplantable neurostimulator 12 of FIG. 1. The external programmer 40includes a healthcare provider operable programming computer 41 and aprogramming wand 42. Generally, use of the external programmer isrestricted to healthcare providers, while more limited manual control isprovided to the patient through “magnet mode.”

In one embodiment, the external programmer 40 executes applicationsoftware 45 specifically designed to interrogate the neurostimulator 12.The programming computer 41 interfaces to the programming wand 42through a wired or wireless data connection. The programming wand 42 canbe adapted from a Model 201 Programming Wand, manufactured and sold byCyberonics, Inc., and the application software 45 can be adapted fromthe Model 250 Programming Software suite, licensed by Cyberonics, Inc.Other configurations and combinations of external programmer 40,programming wand 42 and application software 45 are possible.

The programming computer 41 can be implemented using a general purposeprogrammable computer and can be a personal computer, laptop computer,ultrabook computer, netbook computer, handheld computer, tabletcomputer, smart phone, or other form of computational device. In oneembodiment, the programming computer is a tablet computer that mayoperate under the iOS operating system from Apple Inc., such as the iPadfrom Apple Inc., or may operate under the Android operating system fromGoogle Inc., such as the Galaxy Tab from Samsung Electronics Co., Ltd.In an alternative embodiment, the programming computer is a personaldigital assistant handheld computer operating under the Pocket-PC,Windows Mobile, Windows Phone, Windows RT, or Windows operating systems,licensed by Microsoft Corporation, Redmond, Wash., such as the Surfacefrom Microsoft Corporation, the Dell Axim X5 and X50 personal dataassistants, sold by Dell, Inc., Round Top, Tex., the HP Jornada personaldata assistant, sold by Hewlett-Packard Company, Palo Alto, Tex. Theprogramming computer 41 functions through those componentsconventionally found in such devices, including, for instance, a centralprocessing unit, volatile and persistent memory, touch-sensitivedisplay, control buttons, peripheral input and output ports, and networkinterface. The computer 41 operates under the control of the applicationsoftware 45, which is executed as program code as a series of process ormethod modules or steps by the programmed computer hardware. Otherassemblages or configurations of computer hardware, firmware, andsoftware are possible.

Operationally, the programming computer 41, when connected to aneurostimulator 12 through wireless telemetry using the programming wand42, can be used by a healthcare provider to remotely interrogate theneurostimulator 12 and modify stored stimulation parameters. Theprogramming wand 42 provides data conversion between the digital dataaccepted by and output from the programming computer and the radiofrequency signal format that is required for communication with theneurostimulator 12.

The healthcare provider operates the programming computer 41 through auser interface that includes a set of input controls 43 and a visualdisplay 44, which could be touch-sensitive, upon which to monitorprogress, view downloaded telemetry and recorded physiology, and reviewand modify programmable stimulation parameters. The telemetry caninclude reports on device history that provide patient identifier,implant date, model number, serial number, magnet activations, total ONtime, total operating time, manufacturing date, and device settings andstimulation statistics and on device diagnostics that include patientidentifier, model identifier, serial number, firmware build number,implant date, communication status, output current status, measuredcurrent delivered, lead impedance, and battery status. Other kinds oftelemetry or telemetry reports are possible.

During interrogation, the programming wand 42 is held by its handle 46and the bottom surface 47 of the programming wand 42 is placed on thepatient's chest over the location of the implanted neurostimulator 12. Aset of indicator lights 49 can assist with proper positioning of thewand and a set of input controls 48 enable the programming wand 42 to beoperated directly, rather than requiring the healthcare provider toawkwardly coordinate physical wand manipulation with control inputs viathe programming computer 41. The sending of programming instructions andreceipt of telemetry information occur wirelessly through radiofrequency signal interfacing. Other programming computer and programmingwand operations are possible.

Preferably, the electrodes 14 are helical and placed over the cervicalvagus nerve 15, 16 at the location below where the superior and inferiorcardiac branches separate from the cervical vagus nerve. FIG. 4 is adiagram showing the helical electrodes 14 provided as on the stimulationtherapy lead assembly 13 of FIG. 2 in place on a vagus nerve 15, 16 insitu 50. Although described with reference to a specific manner andorientation of implantation, the specific surgical approach andimplantation site selection particulars may vary, depending uponphysician discretion and patient physical structure.

Under one embodiment, helical electrodes 14 may be positioned over thepatient's vagus nerve 61 oriented with the end of the helical electrodes14 facing the patient's head. At the distal end, the insulatedelectrical lead body 13 is bifurcated into a pair of lead bodies 57, 58that are connected to a pair of electrodes 51, 52. The polarity of theelectrodes 51, 52 could be configured into a monopolar cathode, aproximal anode and a distal cathode, or a proximal cathode and a distalanode. In addition, an anchor tether 53 is fastened over the lead bodies57, 58 that maintains the helical electrodes' position on the vagusnerve 61 following implant. In one embodiment, the conductors of theelectrodes 51, 52 are manufactured using a platinum and iridium alloy,while the helical materials of the electrodes 51, 52 and the anchortether 53 are a silicone elastomer.

During surgery, the electrodes 51, 52 and the anchor tether 53 arecoiled around the vagus nerve 61 proximal to the patient's head, eachwith the assistance of a pair of sutures 54, 55, 56, made of polyesteror other suitable material, which help the surgeon to spread apart therespective helices. The lead bodies 57, 58 of the electrodes 51, 52 areoriented distal to the patient's head and aligned parallel to each otherand to the vagus nerve 61. A strain relief bend 60 can be formed on thedistal end with the insulated electrical lead body 13 aligned, forexample, parallel to the helical electrodes 14 and attached to theadjacent fascia by a plurality of tie-downs 59 a-b.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22. The stored stimulation parameters are programmable. Eachstimulation parameter can be independently programmed to define thecharacteristics of the cycles of therapeutic stimulation and inhibitionto ensure optimal stimulation for a patient 10. The programmablestimulation parameters include output current, signal frequency, pulsewidth, signal ON time, signal OFF time, magnet activation (for VNSspecifically triggered by “magnet mode”), and reset parameters. Otherprogrammable parameters are possible. In addition, sets or “profiles” ofpreselected stimulation parameters can be provided to physicians withthe external programmer and fine-tuned to a patient's physiologicalrequirements prior to being programmed into the neurostimulator 12, suchas described in commonly-assigned U.S. patent application, entitled“Computer-Implemented System and Method for Selecting Therapy Profilesof Electrical Stimulation of Cervical Vagus Nerves for Treatment ofChronic Cardiac Dysfunction,” Ser. No. 13/314,138, filed on Dec. 7,2011, published as U.S. Patent Publication no. 2013-0158618 A1, pending,the disclosure of which is incorporated by reference.

Therapeutically, the VNS may be delivered as a multimodal set oftherapeutic doses, which are system output behaviors that arepre-specified within the neurostimulator 12 through the storedstimulation parameters and timing cycles implemented in firmware andexecuted by the microprocessor controller. The therapeutic doses includea cardiac cycle independent maintenance dose that includescontinuously-cycling, intermittent and periodic cycles of electricalstimulation during periods in which the pulse amplitude is greater than0 mA (“therapy ON”) and during periods in which the pulse amplitude is 0mA (“therapy OFF”).

The neurostimulator 12 can operate either with or without an integratedheart rate sensor, such as respectively described in commonly-assignedU.S. Pat. No. 8,577,458, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction with Leadless Heart Rate Monitoring,” and U.S.patent application, entitled “Implantable Device for ProvidingElectrical Stimulation of Cervical Vagus Nerves for Treatment of ChronicCardiac Dysfunction,” Ser. No. 13/314,119, filed on Dec. 7, 2011,pending, the disclosures of which are hereby incorporated by referenceherein in their entirety. Additionally, where an integrated leadlessheart rate monitor is available, the neurostimulator 12 can provideautonomic cardiovascular drive evaluation and self-controlled titration,such as respectively described in commonly-assigned U.S. patentapplication, entitled “Implantable Device for Evaluating AutonomicCardiovascular Drive in a Patient Suffering from Chronic CardiacDysfunction,” U.S. Patent Publication No. 2013-0158616 A1, Ser. No.13/314,133, filed on Dec. 7, 2011, pending, and U.S. patent application,entitled “Implantable Device for Providing Electrical Stimulation ofCervical Vagus Nerves for Treatment of Chronic Cardiac Dysfunction withBounded Titration,” U.S. Patent Publication No. 2013-0158617 A1, Ser.No. 13/314,135, filed on Dec. 7, 2011, pending, the disclosures of whichare incorporated by reference. Finally, the neurostimulator 12 can beused to counter natural circadian sympathetic surge upon awakening andmanage the risk of cardiac arrhythmias during or attendant to sleep,particularly sleep apneic episodes, such as respectively described mcommonly-assigned U.S. patent application, entitled “ImplantableNeurostimulator-Implemented Method For Enhancing Heart Failure PatientAwakening Through Vagus Nerve Stimulation,” Ser. No. 13/673,811, filedon Nov. 9, 2012, pending, the disclosure of which is incorporated byreference.

Therapeutically, VNS is delivered as a hypertension therapy independentof cardiac cycle and in a maintenance dose having an intensity that isinsufficient to elicit side-effects, such as cardiac arrhythmias. TheVNS can be delivered with a periodic duty cycle in the range of 2% to89% with a preferred range of around 4% to 36% that is delivered as alow intensity maintenance dose. Alternatively, the low intensitymaintenance dose may comprise a narrow range approximately at 10%, suchas around 9% to 11%. The selection of duty cycle is a tradeoff amongcompeting medical considerations. FIG. 5 is a graph 70 showing, by wayof example, the relationship between the targeted therapeutic efficacy73 and the extent of potential side effects 74 resulting from use of theimplantable neurostimulator 12 of FIG. 1. The x-axis represents the dutycycle 71. The duty cycle is determined by dividing the stimulation ONtime by the sum of the ON and OFF times of the neurostimulator 12 duringa single ON-OFF cycle. However, the stimulation time may also need toinclude ramp-up time and ramp-down time, where the stimulation frequencyexceeds a minimum threshold (as further described infra with referenceto FIG. 7). The y-axis represents physiological response 72 to VNStherapy. The physiological response 72 can be expressed quantitativelyfor a given duty cycle 71 as a function of the targeted therapeuticefficacy 73 and the extent of potential side effects 74, as describedinfra. The maximum level of physiological response 72 (“max”) signifiesthe highest point of targeted therapeutic efficacy 73 or potential sideeffects 74.

Targeted therapeutic efficacy 73 and the extent of potential sideeffects 74 can be expressed as functions of duty cycle 71 andphysiological response 72. The targeted therapeutic efficacy 73represents the intended effectiveness of VNS in provoking a beneficialphysiological response for a given duty cycle and can be quantified byassigning values to the various acute and chronic factors thatcontribute to the physiological response 72 of the patient 10 due to thedelivery of therapeutic VNS. Acute factors that contribute to thetargeted therapeutic efficacy 73 include beneficial changes in heartrate variability and increased coronary flow, reduction in cardiacworkload through vasodilation, and improvement in left ventricularrelaxation. Chronic factors that contribute to the targeted therapeuticefficacy 73 include improved cardiovascular regulatory function, as wellas decreased negative cytokine production, increased baroreflexsensitivity, increased respiratory gas exchange efficiency, favorablegene expression, reninangiotensin-aldosterone system down-regulation,anti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatoryeffects. These contributing factors can be combined in any manner toexpress the relative level of targeted therapeutic efficacy 73,including weighting particular effects more heavily than others orapplying statistical or numeric functions based directly on or derivedfrom observed physiological changes. Empirically, targeted therapeuticefficacy 73 steeply increases beginning at around a 5% duty cycle, andlevels off in a plateau near the maximum level of physiological responseat around a 30% duty cycle. Thereafter, targeted therapeutic efficacy 73begins decreasing at around a 50% duty cycle and continues in a plateaunear a 25% physiological response through the maximum 100% duty cycle.

The intersection 75 of the targeted therapeutic efficacy 73 and theextent of potential side effects 74 represents one optimal duty cyclerange for VNS. FIG. 6 is a graph 80 showing, by way of example, theoptimal duty cycle range 83 based on the intersection 75 depicted inFIG. 5. The x-axis represents the duty cycle 81 as a percentage ofstimulation time over stimulation time plus inhibition time. The y-axisrepresents therapeutic points 82 reached in operating theneurostimulator 12 at a given duty cycle 81. The optimal duty range 83is a function 84 of the intersection 75 of the targeted therapeuticefficacy 73 and the extent of potential side effects 74. The therapeuticoperating points 82 can be expressed quantitatively for a given dutycycle 81 as a function of the values of the targeted therapeuticefficacy 73 and the extent of potential side effects 74 at their pointof intersection in the graph 70 of FIG. 5. The optimal therapeuticoperating point 85 (“max”) signifies a tradeoff that occurs at the pointof highest targeted therapeutic efficacy 73 in light of lowest potentialside effects 74 and that point will typically be found within the rangeof a 5% to 30% duty cycle 81. Other expressions of duty cycles andrelated factors are possible.

Therapeutically and in the absence of patient physiology of possiblemedical concern, such as cardiac arrhythmias, VNS is delivered in a lowlevel maintenance dose that uses alternating cycles of stimuliapplication (ON) and stimuli inhibition (OFF) that are tuned to activateboth afferent and efferent pathways. Stimulation results inparasympathetic activation and sympathetic inhibition, both throughcentrally-mediated pathways and through efferent activation ofpreganglionic neurons and local circuit neurons. FIG. 7 is a timingdiagram showing, by way of example, a stimulation cycle and aninhibition cycle of VNS 90, as provided by implantable neurostimulator12 of FIG. 1. The stimulation parameters enable the electricalstimulation pulse output by the neurostimulator 12 to be varied by bothamplitude (output current 96) and duration (pulse width 94). The numberof output pulses delivered per second determines the signal frequency93. In one embodiment, a pulse width in the range of 100 to 250 μSecdelivers between 0.02 and 50 mA of output current at a signal frequencyof about 20 Hz, although other therapeutic values could be used asappropriate.

In one embodiment, the stimulation time is considered the time periodduring which the neurostimulator 12 is ON and delivering pulses ofstimulation, and the OFF time is considered the time period occurringin-between stimulation times during which the neurostimulator 12 is OFFand inhibited from delivering stimulation.

In another embodiment, as shown in FIG. 5, the neurostimulator 12implements a stimulation time 91 comprising an ON time 92, a ramp-uptime 97 and a ramp-down time 98 that respectively precede and follow theON time 92. Under this embodiment, the ON time 92 is considered to be atime during which the neurostimulator 12 is ON and delivering pulses ofstimulation at the full output current 96. Under this embodiment, theOFF time 95 is considered to comprise the ramp-up time 97 and ramp-downtime 98, which are used when the stimulation frequency is at least 10Hz, although other minimum thresholds could be used, and both ramp-upand ramp-down times 97, 98 last two seconds, although other time periodscould also be used. The ramp-up time 97 and ramp-down time 98 allow thestrength of the output current 96 of each output pulse to be graduallyincreased and decreased, thereby avoiding deleterious reflex behaviordue to sudden delivery or inhibition of stimulation at a programmedintensity.

Therapeutic vagus neural stimulation has been shown to beneficiallyreduce hypertension. Although delivered in a maintenance dose having anintensity that is insufficient to elicit side-effects, such as cardiacarrhythmias, therapeutic VNS can nevertheless potentially amelioratepathological tachyarrhythmias in some patients. Although VNS has beenshown to decrease defibrillation threshold, VNS will not terminate VF inthe absence of defibrillation. VNS prolongs ventricular action potentialduration, so may be effective in terminating VT. In addition, the effectof VNS on the AV node may be beneficial in patients with AF by slowingconduction to the ventricles and controlling ventricular rate.

Renal Denervation

Sympathetic activity is believed to be a contributing cause ofhypertension, and interruption of the renal sympathetic nervous systemprovides improved blood pressure control. The renal sympathetic nervoussystem comprises an efferent network component and an afferent networkcomponent. Efferent and afferent renal nerve fibers are generallylocated in the adventitia of the renal arteries, providing communicationbetween the kidney and the brain. Renal denervation has been shown tobeneficially reduce blood pressure.

Referring again to FIG. 1, a patient 10 is illustrated with a rightkidney 102 and a left kidney 103, having respectively a right renalartery 104 and a left renal artery 105. The renal arteries supply bloodto the kidneys, and the renal arteries are normally connected with theabdominal aorta. Although one renal artery is depicted for each kidney,there may be more than one renal artery supplying blood to each kidney.

A renal denervation device 106 is illustrated performing renaldenervation, as is known in the art. According to one embodiment,radiofrequency energy is delivered to the renal arteries via a steerablecatheter comprising an electrode that performs radiofrequency ablation.In some embodiments, the catheter may comprise multiple electrodes. Insome embodiments, the electrode may be positioned on a tip or distal endof the catheter. In addition to delivering energy, an electrode maymeasure impedance and temperature. A renal denervation system may beirrigated, such as when a cooling fluid flows within an electrode, ornon-irrigated. The catheter may enter the arterial system via the groin.A radiofrequency renal denervation device 106 can be adapted from aSimplicity device from Medtronic, Inc.

In an alternative embodiment, a catheter may deliver ultrasound energyto disrupt the nerves in the adventitia of the renal artery. Ultrasoundenergy comprises high-frequency sound waves that pass through fluids andcause heating of soft tissue without direct contact. Ultrasound renaldenervation may promote destruction of renal nerves with minimal damageto a renal artery. In addition, the blood in the artery may act as acoolant for the renal artery. An ultrasound renal denervation device 106can be adapted from a Paradise system from ReCor Medical, Inc.

It is to be understood that disruption of renal nerves may be performedin a variety of ways. For example, a renal artery may be denervated withheat, cold and chemicals, among other nerve disruption mechanisms. Forfurther example, renal arteries may be partially denervated or fullydenervated. For further example, a denervation procedure may be repeatedone or more times, such as to counteract nerve sprouting. For furtherexample, approaches include trans-arterial renal denervation (such asdescribed above), trans-ureteral renal denervation, non-invasive renaldenervation, gamma knife, and nanotechnology. In one embodiment, atransducer positioned outside of the body delivers ultrasound energy toa renal artery. Such a transducer can be adapted from that produced byKona Medical, Inc. In another embodiment, nano magnetic particles may beattached to Botox B as a neurotoxin, which may be injected into therenal arteries. Heat from modulation of a magnetic field may release theneurotoxin and perform renal nerve ablation. In another embodiment,ethanol is used as a neurolysisagent, which is delivered directly to aperivascular space of the renal artery, for example, using a catheterwith microneedles at a distal end. In another embodiment, vascularbracytherapy is performed for ablation of renal nerves by applyingradiation. In another embodiment, instead of inserting a catheter intothe groin, a catheter is inserted via the ureter. In another embodiment,guanethidine may be injected into the adventitia via a microneedle of acatheter. In another embodiment, a neurotrophic agent may be injectedinto the walls of a renal artery, causing neuronal apoptosis. In anotherembodiment, energy may be delivered non-invasively using stereotacticradiosurgery technology, in which target tissue is destroyed withoutharming adjacent tissue. Radiosurgery technology can be adapted from aGamma Knife from Elekta AB, in which an ablative dose of radiation maybe concentrated over a small volume, avoiding damage to nearby tissue.In another embodiment, an electrode may be positioned along an annularspace between a renal artery and a renal fascia, in which a pulsedelectric field is delivered to renal neural fibers to at least partiallydenervate the kidney.

It is to be understood that the forgoing embodiments of ablation ofrenal nerves is not to be limiting, and that other variations ofachieving benefits for treating hypertension by renal denervation, renalnerve ablation, renal nerve disruption, and neural traffic reduction orblockage to and from a kidney do not deviate from the system describedherein.

Treatment Methods

FIG. 8 is a flow diagram showing a method 200 for managing hypertensionthrough vagus nerve stimulation and renal denervation, in accordancewith embodiments of the present invention. The method utilizes thestimulation system 11, the operation of which is parametrically definedthrough stored stimulation parameters and timing cycles.

Preliminarily, at least a portion of a patient's renal nerves areablated utilizing a renal denervation device 106, such as that describedabove (step 202). For example, a procedure may be performed by insertinga catheter in the groin of a patient and placing the catheter in theartery that leads to a kidney. Radiofrequency energy may be applied bythe renal denervation device 106 which may disrupt the renal nerves andmay cause a beneficial reduction in the sympathetic activity of thepatient's nervous system.

Next, an implantable stimulation system 11, which includes aneurostimulator 12, a nerve stimulation therapy lead assembly 13, and apair of electrodes 14, is provided (step 204). In an alternativeembodiment, electrodes may be implanted with no implantedneurostimulator or leads. Power may be provided to the electrodes froman external power source and neurostimulator through wireless RF orinductive coupling. Such an embodiment may result in less surgical timeand trauma to the patient.

The neurostimulator 12 stores a set of operating modes that may includetitration doses and a maintenance dose of the stimulation. Titrationdoses may optionally be delivered for a period of one week, one month,two months, six months, etc. (step 206). Therapy may be up titrated anddown titrated based on the patient's response to the prior renaldenervation procedure in conjunction with the vagus nerve stimulation.Both the down titration and the up titration can occur stepwise, wherethe changes in the stimulation parameters occur in small incrementsspread out over time, rather than all at once. VNS therapy can betitrated by adjusting the stored stimulation parameters, includingoutput current, pulse width, and signal frequency, to different VNStherapeutic setting that are less intense (down titrate) or more intense(up titrate).

In one embodiment, the stimulation protocol may call for a six-weektitration period. During the first three-weeks, the surgical incisionsare allowed to heal and no VNS therapy occurs. During the secondthree-weeks, the neurostimulator 12 is first turned on and operationallytested. The impulse rate and intensity of the VNS is then graduallyincreased every three or four days until full therapeutic levels ofstimulation are achieved, or maximal patient tolerance is reached,whichever comes first. Patient tolerance can be gauged by physicaldiscomfort or pain, as well as based on presence of known VNSside-effects, such as ataxia, coughing, hoarseness, or dyspnea.

Therapy can also be autonomously titrated by the neurostimulator 12 inwhich titration progressively occurs in a self-paced, self-monitoredfashion. During the titration period following post-implantationhealing, the intensity of VNS is incrementally increased in stepwisefashion until a therapeutic goal is reached, the patient feels pain ordiscomfort, or bradycardia or asystole is detected. Ordinarily, thepatient 10 is expected to visit his healthcare provider to have thestimulation parameters stored by the neurostimulator 12 in therecordable memory 29 reprogrammed using an external programmer. Theneurostimulator 12 can be programmed to automatically titrate therapy byup titrating the VNS through periodic incremental increases to thestimulation parameters spread out over time. Up titration, and downtitration as necessary, will continue until the ultimate therapeuticgoal is reached. In some embodiments, up titration doses graduallyapproach a maintenance does, and down titration doses reduce adverseside effects.

Following the titration period, therapeutic VNS, as parametricallydefined by the maintenance dose operating mode, is delivered to at leastone of the vagus nerves (step 208). The stimulation system 11 deliverselectrical therapeutic stimulation to the cervical vagus nerve of apatient 10 in a manner that results in creation and propagation (in bothafferent and efferent directions) of action potentials within neuronalfibers of either the left or right vagus nerve 15, 16 independent ofcardiac cycle.

In one embodiment, the autonomic regulation therapy is provided in a lowlevel maintenance dose independent of cardiac cycle to activate bothparasympathetic afferent and efferent nerve fibers in the vagus nervesimultaneously. In the maintenance dose, a pulse width may be in therange of approximately 250 to approximately 500 μSec delivering betweenapproximately 0.02 and approximately 1.0 mA of output current at asignal frequency in the range of approximately 5 to approximately 20 Hz,and, more specifically, approximately 5 to approximately 10 Hz, orapproximately 10 Hz, and a duty cycle of approximately 5 toapproximately 30%, although other therapeutic values could be used asappropriate.

The physiology of the patient 10 may be monitored during the delivery ofthe maintenance dose. Periodically, the normative physiology of thepatient 10 may be recorded in the recordable memory 29 (shown in FIG.2A). The normative physiology can include heart rate or normal sinusrhythm, as sensed by a physiological sensor, such as a heart ratemonitor 31, as well as other available physiological data, for instance,as derivable from an endocardial electrogram. In a further embodiment,statistics can be stored in the recordable memory 29 for storageefficiency, instead of the raw sensed heart rate data. For instance, abinned average heart rate could be stored as representative of thepatient's overall heart rate during a fixed time period. Based on therecorded normative physiology, a statistical average can be determined.

In a further embodiment, the sensed heart rate data can be used toanalyze therapeutic efficacy and patient condition. For instance,statistics could be determined from the sensed heart rate, eitheronboard by the neurostimulator 12 or by an external device, such as aprogramming computer following telemetric data retrieval. The sensedheart rate data statistics can include determining a minimum heart rateover a stated time period, a maximum heart rate over a stated timeperiod, an average heart rate over a stated time period, and avariability of heart rate over a stated period, where the stated periodcould be a minute, hour, day, week, month, or other selected timeinterval. Still other uses of the heart rate sensor 31 and the sensedheart rate data are possible

In still further embodiments, the suspension and resumption of either orboth the delivery of the maintenance dose can be titrated to graduallywithdraw or introduce VNS. As well, VNS therapy delivery can be manuallysuspended by providing the neurostimulator 12 with amagnetically-actuated reed switch that suspends delivery of themaintenance dose in response to a remotely applied magnetic signal.

The method 200 illustrates the provision of a stimulation system 11(step 204) after surgery to denervate the renal nerves (step 202), thusallowing for titrating therapeutic stimulation doses. Titration dosesmay progressively increase intensity of doses to the vagus nerve. Suchmay be beneficial when the response to the denervation procedure is nothomogenous, and the efficacy of ablation of renal nerves may in somecases be higher while in other cases be lower. Accordingly, theaugmentation of renal denervation with VNS may assist with normalizationof the efficacy of the renal denervation process through up titration,and in the presence of adverse side effects, through down titration.Efficacy may be determined by blood pressure measurements and heartfailure remodeling measurements.

In one embodiment, if vagus nerve stimulation therapy precedes renaldenervation, then the stimulation therapy would be suspended after therenal denervation surgery to allow recovery of the patient from therenal denervation procedure. In another embodiment, because the renalnerves are disrupted by renal denervation, it is believed to bebeneficial to allow the patient's sympathetic and parasympatheticnervous systems to stabilize before beginning the titration process.Such titration of stimulation doses after stabilization of the nervoussystem following renal denervation may avoid adverse side effects suchas bradycardia. In another embodiment, after titration of the vagusnerve stimulation, maintenance doses may be delivered to the patient.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope. Forexample, in various embodiments described above, the stimulation isapplied to the vagus nerve. Alternatively, spinal cord stimulation (SCS)may be used in place of or in addition to vagus nerve stimulation forthe above-described therapies. SCS may utilize stimulating electrodesimplanted in the epidural space, an electrical pulse generator implantedin the lower abdominal area or gluteal region, and conducting wirescoupling the stimulating electrodes to the generator.

What is claimed is:
 1. A method for managing hypertension of a patientthrough vagus nerve stimulation and renal denervation, comprising: atleast partially denervating renal arteries; and delivering stimulationto a vagus nerve, wherein delivering stimulation to the vagus nervecomprises: providing an implantable neurostimulator comprising a pulsegenerator configured to deliver electrical therapeutic stimulation in amanner that results in creation and propagation in both afferent andefferent directions of action potentials within neuronal fiberscomprising the cervical vagus nerve; storing operating modes of thepulse generator in a recordable memory, comprising parametricallydefining a maintenance dose of the electrical therapeutic stimulationtuned to restore cardiac autonomic balance through continuously-cycling,intermittent and periodic electrical pulses; and therapeuticallydelivering the maintenance dose to the vagus nerve independent ofcardiac cycle via the pulse generator comprised in the implantableneurostimulator through at least a pair of electrodes electricallycoupled to the pulse generator via a nerve stimulation therapy lead. 2.A method according to claim 1, further comprising: titrating thestimulation after completing at least partially denervating renalarteries.
 3. A method according to claim 2, wherein the titrating thestimulation comprises up titrating and down titrating until amaintenance dose is reached.
 4. A method according to claim 2, whereinthe delivering stimulation to the vagus nerve comprises: deliveringtitration doses to the vagus nerve in response to the at least partiallydenervating the renal arteries; and delivering maintenance doses to thevagus nerve after the delivering the titration doses to the vagus nerve.5. A method according to claim 4, wherein the delivering the titrationdoses comprises progressively increasing intensity of the titrationdoses to the vagus nerve.
 6. A method according to claim 4, wherein theresponse to the at least partially denervating the renal arteriescomprises an efficacy, and wherein the delivering titration doses to thevagus nerve comprises normalizing the efficacy.
 7. A method according toclaim 6, wherein the efficacy is determined by a blood pressuremeasurement.
 8. A method according to claim 6, wherein the efficacy isdetermined by a heart failure remodeling measurement.
 9. A methodaccording to claim 6, wherein the normalizing the efficacy comprises uptitration and down titration.
 10. A method according to claim 1, whereinthe at least partially denervating the renal arteries precedes thedelivering the stimulation to the vagus nerve.
 11. A method according toclaim 1, wherein the at least partially denervating renal arteriescomprises ablating renal nerves with radiofrequency energy.
 12. A methodaccording to claim 11, wherein the ablating renal nerves with theradiofrequency energy comprises positioning at least one electrode in arenal artery.
 13. A method according to claim 12, wherein thepositioning the at least one electrode in the renal artery comprisespositioning a catheter comprising the at least one electrode in therenal artery.
 14. A method according to claim 1, wherein the at leastpartially denervating renal arteries comprises ablating the renal nerveswith ultrasound energy.
 15. A method according to claim 14, wherein theablating the renal nerves with the ultrasound energy comprisespositioning a transducer external to the patient.
 16. A method accordingto claim 1, wherein the at least partially denervating renal arteriescomprises ablating the renal nerves with a chemical.
 17. A methodaccording to claim 16, wherein the ablating the renal nerves with thechemical comprises positioning at least one microneedle in a renalartery.
 18. A method according to claim 1, wherein the at leastpartially denervating renal arteries comprises disrupting renal nervesto inhibit a sympathetic nervous system.
 19. A method according to claim1 , further comprising: prior to the therapeutically delivering themaintenance dose, delivering titration doses to the vagus nerve inresponse to the disrupting the renal nerves, the titration dosescomprising: up titration doses to gradually approach the maintenancedose; and down titration doses to reduce adverse side effects.
 20. Amethod according to claim 1, wherein the disrupting the renal nervescomprises: positioning a catheter within a renal artery, the cathetercomprising at least one electrode; positioning the at least oneelectrode proximate to at least one of the renal nerves; energizing theat least one electrode; and removing the catheter from within the renalartery.